The radiotherapeutic treatment of cellular disorders, including cancer and infectious diseases is widely documented in literature. A variety of methods have been developed in order to utilise radionuclides in radiotherapy, including targeted radiotherapy, pre-targeted radiotherapy and the use of radionuclides in the form of bone-seeking complexes.
Targeted alpha therapy (TAT) is a site directed treatment modality for cellular disorders, including cancer and infectious diseases, using alpha radiation to selectively destroy targeted cells, e.g. tumour cells, fungal cells or bacteria. The principle of TAT is based on the coupling (also referred to as binding or linking) of alpha-emitting radionuclides to targeting moieties, e.g. monoclonal antibodies or peptides, that recognise a structure in, on or near a target. Due to the short path length of alpha particles in human tissue (<100 μm), TAT has the potential of delivering a highly cytotoxic radiation dose to targeted cells, while limiting the damage to surrounding healthy tissue. Several pre-clinical and clinical studies have shown the feasibility of TAT for the treatment of various types of cancer [Ref. 9, Ref. 11, Ref. 1, Ref. 16, Ref. 12] and infectious diseases [Ref. 5].
Several reports [Ref. 15, Ref. 17, Ref. 18] have shown the potential of pre-targeting techniques for radiotherapy. Pre-targeting techniques, typically using the high affinity of avidin-biotin binding, show the potential for the rapid and selective delivery of radionuclides to target sites leading to the reduction of radiation delivered to normal tissues. Pre-targeted radiotherapy is therefore especially well suited for applications using short-lived radionuclides. A promising approach for pre-targeted radiotherapy, as reported by the NeoRx Corporation (Seattle, Wash., USA) consists of three steps. In step 1, an antibody-streptavidin (SA) conjugate is administered intravenously and allowed to target and accumulate in the tumour. In step 2, a synthetic biotinylated clearing agent is administered to clear unbound antibody-SA from the circulation in vivo. The resultant complexes are rapidly cleared into the liver and metabolized. In step 3, the radionuclide is delivered to the tumour site by administration of radiolabeled biotin, a low molecular weight molecule that rapidly reaches and binds to antibody-SA pre-localized at the tumour site [Ref. 18].
Other known variants of pre-targeted radiotherapy are:                the injection of a biotinylated monoclonal antibody in the first step, followed by the administration of avidin to avidinylate the tumour and by injection of radiolabelled biotin in the third step [Ref. 25].        a 5-step strategy as follows: (1) injection of biotinylated antibody; (2) administration of avidin to clear biotinylated antibody from circulation; (3) injection of streptavidin to avidinylate the tumour; (4) clearing of circulating streptavidin by biotinylated albumin and (5) injection of radiolabelled biotin [Ref. 26]        the use of bi-specific antibodies for tumour targeting with one binding site and accumulation of a radiolabelled peptide by the second binding site [Ref. 22].        
A further application of alpha-emitting radionuclides for radiotherapy is the administration of bone-targeting complexes of alpha-particle emitting radionuclides in therapeutical, prophylactic or pain-palliating amounts, e.g. for the treatment of calcified tumours, bone tumours, bones, bone surfaces and soft tissues as described e.g. in WO 03/105762. By bone-targeting it is meant that the radionuclide complex distributes preferentially to the bone as opposed to soft tissue organs, in particular liver, spleen and kidney.
Bone metastases are frequent in cancer patients. Chemotherapy, external radiotherapy or hormone therapy induce temporary responses, but ultimately most patients relapse. As a result, new therapies are required to inhibit tumour progression and to relieve pain.
The use of radionuclides for the treatment of bone metastases in cancer patients seems to be promising. P-32-orthosphosphate, Sr-89-chloride, Sm-153-EDTMP (ethylenediaminetetramethylene phosphonic acid), Re-186-HEDP (hydroxyethylidene diphosphate) and Re-188-HEDP have already been used in clinical trials with benefits in palliation of osseous metastases [Ref. 10]. The bone-seeking properties of the nuclides are based on their elemental nature or on the chemical properties of an attached ligand. They are preferentially incorporated into bony lesions undergoing new bone formation compared with normal bone. Administered intravenously as a systemic approach, the radionuclides offer the opportunity to treat several lesions simultaneously, as most patients with skeletal metastases have multiple localizations.
The effects of bone-targeting radiopharmaceuticals based on beta-emitters include, due to their long radiation range, a significant exposure of the bone marrow leading to hematological toxicity. Alpha-emitters are a possible alternative. At-211 linked to bisphosphonates [Ref. 21], Bi-2,2-DOTMP [Ref. 19], Ra-223 [Ref. 20] and Ra-224 [ref. 14] have already been evaluated as bone-seeking agents.
Today, a main impediment for the use of alpha-emitters in radiotherapy is the limited availability of suitable alpha-emitting radionuclides in sufficient quantities for widespread medical use. Among the alpha-emitters presently considered for radiotherapy, including Tb-149, Ra-223, At-211, Bi-213, Ac-225 and others, Bi-213 (half-life T1/2=46 min), available through the decay chain of Ac-225 (T1/2=10 days), is presently the most promising. The bottleneck for the widespread use of the Ac-225/Bi-213-pair in radiotherapy has been the limited availability of the mother radionuclide Ac-225. Presently, Ac-225 can be obtained only in limited quantities (approx. 1 Ci per year) by radiochemical separation from Th-229 sources available at the Institute for Transuranium Elements in Karlsruhe, Germany and Oak Ridge National Laboratory, USA [Ref. 2, Ref. 4].
These facts severely limit the progressing of studies investigating TAT.
To further advance the application of TAT, alternative radionuclides need to be found that can be produced in technical simple way in sufficient quantity and purity, that can be combined to targeting moieties in a stable manner, and that have decay characteristics that allow their use in humans.